Luteal phase defect (LPD) is often diagnosed in infertile women, and substantial resources are devoted to its treatment. However, neither the link between LPD and infertility nor the efficacy of LPD treatment is well established. Evaluation of a link between LPD and infertility has been hampered by inadequate data in the prevalence of LPD in infertile women, and studies of LPD treatment efficacy have been limited by the absence of placebo-controlled trials. To address these important gaps in our knowledge about LPD, the aims of the project are: to estimate the relative risk of infertility from LPD by comparing the rate of LPD in infertile women with that in matched group of fertile women (Study 1); and to estimate the efficacy of LPD treatment in infertile women using a prospective randomized, placebo-controlled design (Study 2). A multicenter network of six Clinical Reproductive Medical Units (RMUs) will each contribute subjects to achieve a sample size sufficient to adequately address these aims. In Study 1, a total of 180 menstruating, infertile women who have not been surgically sterilized and 180 fertile controls taken from the same clinical practices will be recruited. Daily samples for serum progesterone in the luteal phase and timed endometrial biopsies will be taken from all subjects. Receiver operating characteristic analysis will be used to select the best measure of LPD, and an appropriate threshold value. This threshold will then be used to calculate the relative risk of infertility from LPD. If it is concluded from STudy 1 that LPD has a significant association with infertility, a total of 120 infertile women will be recruited for Study 2, which is designed to determine whether treatment of infertile women with LPD improves the likelihood that they will conceive. A randomized, within-subject, placebo- controlled design will be used to assess LPD treatment efficacy. Using a mathematical model of cumulative pregnancy rates, the outcome of treatment and placebo cycles will be compared. Given the large number of infertile women currently undergoing evaluation and treatment of LPD, and thus exposed to the associated costs and risks, it is important to confirm that LPD is an important contributor to infertility, and if so, to determine whether treatment is efficacious.